Nikhil Kumar Palakurthi

Toxicity of a biodegradable microneedle implant loaded with methotrexate as a sustained release device in normal rabbit eye: a pilot study.

PURPOSE Primary intraocular lymphoma is a term that refers to nonmetastatic malignant lymphoid neoplasia that arises primarily within the eye. Primary vitreo-retinal lymphoma (PVRL), a subtype of primary intraocular lymphoma that comprises at least 85% of cases, provides a therapeutic challenge because of its diverse clinical presentations and variable clinical course. One of the currently available treatment options for PVRL is intravitreal injection of methotrexate. To achieve and maintain sufficient therapeutic levels of methotrexate in the eye to eradicate PVRL, the patient must undergo multiple intravitreal injections with attendant potential toxic peaks and sub-therapeutic troughs of intraocular drug concentrations. In this pilot study, we investigated the intravitreal concentration of methotrexate over time, and toxicity associated with slow sustained release of the drug from a biodegradable device containing methotrexate implanted in a deep scleral pocket of the eyes of normal rabbits. METHODOLOGY Biodegradable microneedle implants (~8 mg) loaded with 10%wt of methotrexate were fabricated using solvent cast method. All the implants were inserted surgically in a deep lamellar scleral pocket created in each eye of 3 albino New Zealand rabbits. The left eye received a placebo implant, and the right eye received an implant loaded with methotrexate. Postoperatively, the animals were monitored regularly for complications related to the surgery, implant, or drug. The animals were sacrificed 4 weeks after the surgical implantation, and the eyes were enucleated. The eyes were studied histopathologically to look for evidence of inflammation related to the implants and toxicity related to the implant or drug. RESULTS The biodegradable microneedle methotrexate implants were inserted successfully into deep lamellar scleral pockets of the rabbits without any intraoperative or postoperative complications. Histopathologic examination of the medicated (methotrexate implant) and nonmedicated devices (placebo) showed no evidence of drug toxicity. Also, no major differences were apparent between the eyes as well as no acute ocular inflammation or infection was evident around the implantation site. CONCLUSIONS This sustained release implant containing methotrexate proved to be nontoxic histopathologically and well-tolerated in the eyes of normal rabbit.

Investigation of Kinetics of Methotrexate for Therapeutic Treatment of Intraocular Lymphoma

Purpose: Primary intraocular lymphoma (PIOL) provides a therapeutic challenge because of its diverse clinical picture and variable clinical course. The main objective of this study was to evaluate the retinal permeability of methotrexate for rabbit and human eyes and then investigate its kinetics in a human eye following the standard induction–consolidation–maintenance (I-C-M) injection protocols for the treatment of PIOL. Additionally, the therapeutic release rate of a 90-day sustained-release methotrexate implant was also determined for the effective treatment of PIOL. Methodology: The 3-dimensional model of a rabbit eye was adapted from our previous studies and a human eye model was constructed based on its physiological dimensions. The retinal permeability of methotrexate was the only unknown parameter in the numerical calculations and was determined by comparing the model simulated vitreous concentrations for rabbit and human eyes with the available in vivo and clinical data, respectively. Results: The retinal permeability values of methotrexate calculated for an albino rabbit and human eye were 1.1 × 10−5 cm/s and 9.25 × 10−6 cm/s, respectively. Given that the dosage above 0.1 µM is considered tumoricidal, the cytotoxic levels of methotrexate were consistently achieved only in the induction phase and the concentration levels dropped below the cytotoxic levels for part of the consolidation and maintenance phases of the treatment following the I-C-M protocols. A sustained-release implant with a mean release rate of 0.2 μg/day–2 μg/day should be designed in order to maintain tumoricidal levels of methotrexate inside the vitreous of the human eye for a period of 3 months. Conclusions: By making use of the results of this study, one could select a dosing interval for serial injections of methotrexate or establish a treatment schedule using a controlled release methotrexate implant for the treatment of PIOL.

A Feasibility Study of the Pore Topology Method (PTM), A Medial Surface-Based Approach to Multi-phase Flow Simulation in Porous Media

Computationally efficient microscale models designed to simulate multi-phase flow and characterize low-porosity media are challenged in thin, highly porous materials, primarily due to large, irregular pore spaces and inability to satisfy representative elementary volume requirements. In this article, we describe the pore topology method (PTM) and explore its capabilities to characterize a set of isotropic fibrous materials and to simulate multi-phase flow. PTM is a fast, algorithmically simple method that reduces the complexity of the 3-D void space geometry to its topologically consistent medial surface and uses it as a solution domain for single- and multi-phase flow simulations. Our results in permeability calculations, pore size distribution, and quasi-static drainage and imbibition simulations are in very good agreement with other numerical methods and analytical solutions. We expect that incorporating detailed spatial information about the porous media structure into the medial surface will enable a more accurate representation of the void space structure and of physical phenomena involved in multi-phase flow, thus expanding the applicability of PTM to a broader range of porous media, including non-fibrous materials.